Process for preparing substituted furo-imidazoles



Patented Aug. 29, 1950 UNITED STATES PATENT OFFICE PROCESS FOR PREPARING SUBSTITUTED I FURO IMIDA ZOLES Klaus Hofnian, Pittsburgh, Pen, assignor to Cilia Pharmaceutical Products, Incorporated, Sinnmit, N. J., a corporation orNew Jersey No Drawing. Application April 4, 1945', Serial No. 586 829 3 Claims. (01. Zet -309") 1 ing azide into the 3,4-d iamino carbalkoxy derivative which by catalytic hydrogenation is converted to the saturated analogs III. The latter may be converted to thecorresponding 3,4-diamino compound II by hydrolysis. I I

It has been found that ring closure to produce compound I may be readily effected from either compoundfi or compound III, according to the general scheme: l

The present application is part a continuation of co-pending application, Serial No. 5l.1,6l0, filed on November 24, 1943 (now U. S.- Pat. No. 2,432,016, granted December 2, 1947), and the invention to which the present application relats is a further development of the inventionde-, scribed and claimed in said copending application.

A primary object of the present invention is to develop synthetical procedures for the prepara- Preferred procedures according to the invention involve the treatment of compound II in an alkaline solution With phosgene whereby the desired ring closure takes place. The same ring closure to form the imidazole ring can be efiectd by heating compound II with an equimolar amount of diethyl carbonate. The ring closure can also be accomplished by treating a compound III witlr o an alkaline agent at elevated temperature, and it with especial reference from the product stand- P l mh l m p e invention point to those situations wherein R1 represents a m j f f 3 2 fi i d- V l (II-1201i group and 1: represents the in eger 4, n swa s rti ma P Ts l mifi from the process standpoint to the step of close tetrahydrofurans 0f the general formulae II andtion of new and particularly useful biotin analogs of the general formula 1 EN/ liih hri mg the I III wherein R1 stands for a-liydroger'iatom,a car- O0 boxyl group or a group, preferably --CH2OI-I,

can be transformed into a carboxyl group;

- R2 standsfor an alkyl group such as methyl;

H l I H ethyl, isopropyl, etc'., or an aralkyl group s-uchas;

phenylethyl, etc., or an aryl group such as phenyl, para-tol l, etc-., and rsta-n'ds for one of the num: bers 1 6", inclusive. v

Among the groups which can be transformed to a carboxyl group the following ones may be mentioned: aliphatic and aromatic ester groups such as methyl, ethyl, propyl, phenyl, benzyl ester groups; aliphatic and aromatic amide groups such as amide, monoand dimethyl amide, diethyl amide, piperidide', anil'ide, N-methylanilide groups; nitrile group; hydroxyl group; halogen ring of the correspondingly z-substituted 3,4-dianiino-tetrahydrofuran II or 3 ,4-diamino=carball roxy-tetrahydrofuran IIIuse being preferably made of the cis compound, the term fois being 40 here employed with reference to the relative posi: tions of the amino or substituted amino groups The aforesaid compounds II and III may be repared, for example; according to the disclosure 46 of coperiding application, Serial No.

2-subsi-ue ifii a r lf h la t tgr i s o h i n t gr first reacted group; y e group and derivatives thereof With an acetylene-d'icarboxyli'c acid ester, there such as h acetal gr W sultant com lex being thenpartiaily hydrogen- 60 the? tmhsfermahon 0f h u ha interated with the aid of a catalyst, whereupon the) medlate 0f r l III n l B-i hydrogenated compound is distilled to eliminate I 'aj I t f llowmg alkaline agents havaicr ne. one molecule of ethylene and reproducethe cor p been? u o' h hydroxldesoi responding Z SubStituted; iuran-M-dicarboxylie the k and alkahne earth tals, sp ially ester. Treatment of the latter with ahydro-lizi'rlg barium hydroxide,butalsocalciumlhydroxideandr agent and then with thionyl' chloride produces sodium hydroxide. l the corresponding 3',4-dicarboxylic acid chloride; The" new compoundsare use'iulfor thepreparae which may be converted through the-correspond: tiorr or substances which are valuable ior thera' peutic purposes or as intermediates in the production of such substances.

The following examples illustrate methods of carrying out the present invention, but it is to be understood that the examples are given by way of illustration and not of limitation.

Example 1 1.28 g. of cis-3,4-diamino-carbethoxy-2-methyltetrahydrofuran were heated on the steam bath for two hours with a solution of 6.3 g. of barium hydroxide.8HzO in 50 cc. of water. The excess of barium hydroxide was removed with CO2 and the barium carbonate was removed by filtration. The filtrate was concentrated to dryness in vacuo and the resulting hexahydro-Z-oxo-4-methyl-1- furo-[3,4]-imidazo1e, having a melting point of 228-230 C. was purified by sublimation in vacuo at 150-160 C. at 0.005 mm,

Example 2 3.32 g. of cis-3,4-diaminocarbethoxy2-tetrahydrofuranpentanol were treated with 12.6 g. of barium hydroxideBHzO in 100 cc. of water as described in Example 1. The resulting hexahydro 2 oxo 1 furo [3,4] imidazole 4 pentanol of a melting point of 154-155 C. was purified by crystallization from dioxane. It has the following formula f3 HN NH 4.1.3 g. of cis-3,4-diaminocarbethoxy-2-tetrahydrofuranvaleric acid-piperidide were heated for 20 hours to 130-140 C. in a sealed tube with a concentrated barium hydroxide solution. The formed barium carbonate was removed by filtration and the liberated piperidine was removed by ether extraction. The aqueous residues were treated with CO2 to precipitate the excess of barium hydroxide, and the resultant barium carbonate was filtered oil. The filtrate was concentrated to dryness in vacuo, the residue was dissolved in 50 cc. of ice cold sodium bicarbonate and the solution was treated with phosgene. The hexahydro -2- oxo-1-furo-[3,4]- imidazole-4-valeric acid of a melting point of 210-211 C. which crystallized from the solution was collected and recrystallized from water. It has the formula Example 4 3.28 g. of 3,4-diaminocarbethoxy 2 furanpentanol were hydrogenated in 100 cc. of glacial acetic acid in the presence of a hydrogenating catalyst of the platinum group, e. g. palladium on charcoal, until an amount of hydrogen corresponding to two mols had been absorbed. The catalyst was removed by filtration and the glacial acetic acid was removed in vacuo. The residue was dissolved in ethyl acetate, and, the solution was washed with 10% sodium bicarbonate, dried over sodium sulfate, and the ethyl acetate was removed in vacuo. The resulting oil which contained cis-3,4-diaminocarbethoxy -2- tetrahydrofuranpentanol was treated with a solution of 12.6 g. of barium hydroxide.8H2O in 100 cc. of water for two hours at 100 C. The excess of barium hydroxide was removed with CO2 and the clear filtrate on concentration gave hexahydro-Z-oxo- 1-furo-[3Alimidazole-4-pentanol of a melting point of 154-155 C. which was identical with the material described in Example 2.

2.14 g. of the above hexahydro-Z-oxo-l-furo- [3,4l-imidazole 4 pentanol were dissolved in 100 cc. of N/10 sodium hydroxide. 64 cc. of a 5% solution of potassium permanganate were slowly added and the solution was kept at room temperature over night. The M1102 was removed by filtration and the clean filtrate was concentrated to a small volume in vacuo. The residue was acidified to Congo red with concentrated hydrochloric acid and the hexahydro-2-oxo-1- furo-[3,4]-imidazole-4-valeric acid of a melting point of 210-211 C. which separated from the solution was purified by crystallization from water. The material was identical with the material described in Example 3.

Example 5 4-methyl-l-furo [3,4] imidazole of a melting in Example 1.

point of 228-230 C. was isolated by sublimation in vacuo at 150-160 C. at 0.005 mm. The material was identical with the product described Example 6 1.0 g. of cis-3,4-diamino-2-tetrahydrofuranvaleric acid sulfate was treated with phosgene in 10% sodium bicarbonate as described in Example 5. The resulting hexahydro-Z-oxo-lfuro-[3,4]-imidazole-4-valeric acid of a melting point of 210-211 C. separated from the solution and was purified by crystallization from water. The material was identical with the product obtained according to Examples 3 and 4.

Example 7 3.18 g. of cis- 3,4-diaminocarbethoxy-2-tetrahydrofuranbutanol were dissolved in a solution of 12.6 g. of barium hydroxide.81-I2O in 100 cc. of water, and the solution was heated at 100 C. for two hours. The excess barium hydroxide was removed with CO2, and the barium carbonate was filtered oil. The clear filtrate was concentrated to dryness in vacuo, and the residue was extracted with three 50 cc. portions of hot dioxane. Concentration of the combined dioxane extracts gave the desired hexahydro-Z-oxo-lfuro- [3,4] -imidazole-4-butanol.

2.0 g. of the above hexahydro-2-oxo-1-furo- [3,4] -imidazole-4-butanol were dissolved in 100 cc. N/10 sodium hydroxide, and 64 cc. of a 5% solution of potassium permanganate were slowly added. The solution was kept at room temperature over night, was filtered, and the clear filtrate was acidified to Congo red with concentrated HCl. The desired hexahydro-2-oxo-1-furo-[3,4]-

imidazole-A-butyric acid crystallized when the above solution was concentrated to a small volume in vacuo.

Example 8 1.78 g. of ole-3,4-diaminocarbophenoxy-Z-methylfuran were treated with a mixture of 1.48 g. of calcium hydroxide in 100 cc. of water and 50 cc. of dioxane and then heated on the steam bath for two hours. Most of the excess of calcium hydroxide was removed with CO2, the calcium carbonate was removed by filtration, and the clear filtrate was concentrated to dryness in vacuo. The resulting hexahydro-2-oxo-4-methyll-furo-[3A] -imidazole of a melting point of 228-230 C. was purified by sublimation in vacuo at 150-160 C. and 0.005 mm, and was identical with the compound described in Example 1.

Having thus described the invention, what is claimed is:

1. In a process for the manufacture of a biotin analog, the step of subjecting a urethan of the general formula wherein R1 is a member of the group consisting of hydrogen, a carboxyl group and a group convertible into a carboxyl group, :0 is one of the integers 1, 2, 3, 4, 5 and 6, and R2 is a member of the group consisting of alkyl, aralkyl and aryl, to treatment with an alkaline agent at elevated temperature to produce the corresponding 4-substituted 2,3,3a,4,6,6a hexahydro 2 0x0 1- furo- [3,4] -imidazole.

6 2. In a process for the manufacture of a biotin analog, the step of subjecting a urethan of the general formula wherein a: is one of the integers l, 2, 3, 4, 5 and 6 and R2 is a member of the group consisting of alkyl, aralkyl and aryl, to treatment with an alkaline agent at elevated temperature: to produce the corresponding 4-substituted-2,.3,3a,4,6,- Ga-hexahydro-2-oxo-1-furo [3,4] -imidazole.

3. In a process for the manufacture of a biotin analog, the step of subjecting a urethan of the general formula No references cited.

Certificate of Correction Patent No. 2,520,404 August 29, 1950 KLAUS HOFMANN It is hereby certified that error appears in the above numbered patent requiring correction as follows: 7

In the grant, line 1, and in the heading to the printed specification, line 4, name of inventor, for Klaus Hofman read Klaus Hofmann; in the signature to the specification, for KLAUS HOFMAN read KLAUS HOFMANN;

and that the said Letters Patent should be read as corrected above, so that the same may conform to the record of the case in the Patent Oflice.

Signed and sealed this 28th day of November, A. D. 1950.

THOMAS F. MURPHY,

Assistant Commissioner of Patents. 

1. IN A PROCESS FOR THE MANUFACTURE OF A BIOTIN ANALOG, THE STEP OF SUBJECTING A URETHAN OF THE GENERAL FORMULA 